The Meyer-Overton hypothesis states that lipophilicity determines the potency of an inhaled anesthetic, and that the product of some index of potency (e.g., MAC, the minimum alveolar concentration of anesthetic that abolishes movement in response to a noxious stimulus in 50% of animals) and lipophilicity (e.g., the oil/gas partition coefficient) equals a constant. For the past century, this hypothesis has provided a basis for several theories of narcosis. Results from our preliminary studies indicate that the historical form of the hypothesis is no longer tenable. We have discovered inhalational compounds that are not anesthetics (non- anesthetics) despite oil/gas partition coefficients that indicate that they should provide anesthesia, and compounds that are less potent than would be predicted from their lipophilicity (transitional compounds). At the other extreme, we find alkanols that are more potent that would be predicted by Meyer and Overton. Our hypothesis is that anesthesia as defined by MAC is determined by a combination of lipophilicity and hydrophilicity, and that no single representation of the site of anesthetic action (e.g., olive oil or n- octanol) can predict anesthetic potency. We base this on our results that show that non-anesthetics have an extraordinarily low affinity for water (a low saline/gas partition coefficient), transitional compounds have a higher affinity (but lower than that found for conventional anesthetics), while alkanols have an extraordinarily high affinity. We propose to confirm these findings and develop a select pool of non- anesthetics, transitional compounds, and anesthetics in each of specific haloalkane, halocycloalkane and haloether series. Each series plus the alkanol series will be used by all investigators in this Program project to test the relevance of a putative site of anesthetic action. A relevant site would not be affected by non-anesthetics, but should be affected by transitional and anesthetic compounds in proportion to their anesthetic potency. We also will use the non-anesthetics to explore differences in sites and mechanisms that control two other important aspects of anesthesia: central nervous system excitation, and depression of ventilation.